HIV prevention efforts, including vaccine, microbicide and co-infection prophylaxis strategies, have yielded disappointing results, highlighting the need for new concepts. To this end, a better understanding of early events in HIV infection, including HIV acquisition in the face of an existing HIV infection (superinfection) are needed. Superinfection, in particular, offers an opportunity to examine immune correlates of protection based on responses to the initial infection. Our research team is in unique position to address such questions because we have developed and maintained a cohort of ~ 2000 women at high-risk of HIV infection for the past 15 years. This cohort includes more than 300 women who have known dates of HIV infection and who have been followed closely, including regular sample collection for a median of 4.4 years after their infection. Importantly, 12 cases of superinfection were identified in the first 56 women examined in this cohort, including both intra and intersubtype re-infections. Here we propose to continue monitoring this unique cohort and leveraging existing samples to examine factors that influence early virus control and the incidence of superinfection and its correlates. Specifically, we propose to examine the role of early humoral immune responses, particularly antibodies that contribute to Fc-mediated antibody activity, in viral control and disease progression. We propose to examine the role of these same immune parameters in cases of superinfection to determine if there are deficits in humoral immunity in those who become superinfected. A major emphasis of our studies will be in determining whether a first HIV infection provides any protection from a second infection by determining if the incidence of superinfection is lower that the incidence of initial infection. We propose to examine whether there are cases of transient superinfection, and if so, whether antibody responses may play a role in viral control in this setting. Together, these studies will provide critical data on the role of Fc-mediated antibody activity in defining early virus control and subsequent disease as well as their potential role in protection from infection. PUBLIC HEALTH RELEVANCE: These studies will help determine whether the host response to natural HIV infection provides any protection against subsequent infection. The studies are also designed to define the nature of any protective humoral immune response, if present, with the goal of using such information to inform future vaccine and prevention strategies.